Opiate abuse and HIV-1 have been described as two linked global health crises, and despite the advent of anti-retroviral therapy, abuse of opiates has been shown to result in increased neurologic and cognitive deficits. Using the morphine-dependent rhesus macaques (RMs) infected with CCR5-utilizing SIVR71/17E we recapitulated the human syndrome demonstrating augmentation of neuropathology & neuroinflammation and rapid disease progression compared with SIV-infected RMs without opiate dependence. Mortality in these rapid progressors was associated with robust microglial activation and neuronal injury. MicroRNA (miR)- mediated regulation of disease pathogenesis represents an evolving area of research that has ramifications for identification of potential therapeutic target for various neurodegenerative disorders for which currently there exists no cure. Herein we hypothesize that morphine & HIV Tat modulate increased neuropathology via two complementary mechanisms: a) Morphine exposed astrocytes upregulate expression & release of miR-138 in the extracellular vesicles (EVs), which, following uptake by the microglia, results in their activation via the TLR7-dependent pathway and, b) HIV Tat exposed astrocytes upregulate expression & release of miR-9 in the EVs, that are taken up by the microglia, leading in turn, to increased microglial migration. Two experienced PIs will join on this project to investigate this hypothesis. The innovative aspects of this proposal are based on our unique observation that in chronically (SIV)-infected rhesus macaques, morphine mediated potentiation of neuropathogenesis correlates with dysregulation of miRs, with specific upregulation of miR-138 & miR-9 in the post mortem brain tissues from SIV and morphine-dependent macaques, respectively. These experiments will be brought full circle with the examination of functional studies to examine the mechanisms uncovered in a rodent model of HIV Tat/morphine exposure. This proposal is responsive to the RFA, focusing on release of EVs in HIV/AIDS and including a drug of abuse (morphine).